Control of gene expression in a sequence-specific manner by silencing with small interfering RNA (siRNA) in living cells holds great promise both as a novel therapeutic approach and as a new instrument for a drug target discovery. Cellular and animal models demonstrate the potential application of siRNA-based therapies for cancer, viral infections and inflammatory diseases. The advancement of siRNA-based therapeutics into the clinic is hampered by two significant obstacles. One obstacle takes the form of non-specific, that is “off-target,” binding of siRNAs to unintended mRNAs. Such non-specific binding that leads to partial or complete silencing accompanied by unwanted cytotoxic effects. Another obstacle is the lack of the means for the targeted delivery of a stable siRNA into a diseased tissue (e.g., tumor), but not into the adjacent normal cells or connected organs. Thus, improvements in siRNA engineering and delivery are needed to realize the potential of siRNA-based therapies.